Parkinson's Disease - MBBS 1st Year Guide

1. Definition & Overview

• Onset typically between 55-65 years of age
• It is the second most common neurodegenerative disorder after Alzheimer's disease

2. Anatomy & Neurotransmitter Basis

The Nigrostriatal Pathway

• Pars compacta - contains pigmented dopaminergic neurons (site of degeneration in PD)
• Pars reticulata - inhibitory output nucleus

• Substantia nigra pars compacta sends dopaminergic (inhibitory) projections to the neostriatum
• Neostriatum sends GABAergic (inhibitory) neurons back to the substantia nigra
• This mutual inhibitory circuit normally maintains balanced motor control

Figure: Role of the substantia nigra in Parkinson disease. DA = dopamine; ACh = acetylcholine; GABA = γ-aminobutyric acid. - Lippincott Illustrated Reviews: Pharmacology

1. Dopaminergic neurons in the substantia nigra degenerate and die
2. Dopamine levels in the neostriatum fall
3. The normal inhibitory effect of dopamine on cholinergic (ACh) neurons is lost
4. Cholinergic neurons become relatively overactive (ACh > DA imbalance)
5. This abnormal signaling disrupts the motor control circuit → motor symptoms

3. Pathology (What You See Under the Microscope)

Gross Pathology

• Pallor/depigmentation of the substantia nigra (normal black pigment from neuromelanin is lost due to neuronal death)

Microscopic Pathology - Lewy Bodies (PATHOGNOMONIC)

• Lewy bodies are intracytoplasmic, eosinophilic (pink) inclusions with a dense center and a lighter surrounding halo, found in remaining dopaminergic neurons
• Composed mainly of alpha-synuclein protein
• This is the hallmark lesion of Parkinson's disease

(A) Midbrain section showing pallor/asymmetric depigmentation of the right substantia nigra. (B) Microscopic Lewy body - dense pink center with lighter halo inside a pigmented neuron. (C) DaT SPECT scan showing asymmetric reduced dopamine uptake. - Neuroanatomy through Clinical Cases 3e

4. Etiology

• Idiopathic in most cases (cause unknown)
• Genetic factors: Mutations in LRRK2, SNCA (alpha-synuclein), PARK genes
• Environmental: MPTP (a neurotoxin), pesticides (rotenone, paraquat)
• Secondary (Drug-induced) Parkinsonism: Antipsychotics (haloperidol, phenothiazines) - block dopamine receptors; called pseudoparkinsonism

5. Clinical Features - "TRAP"

Additional Motor Signs

• Masked facies (hypomimia) - reduced facial expression, decreased blink rate
• Micrographia - small handwriting
• Festinating gait - short, shuffling steps, appears to be "chasing their center of gravity"
• Freezing - difficulty initiating gait
• Hypophonia - soft, monotonous voice
• Myerson's sign - inability to suppress blinking when the glabella is tapped repeatedly
• Stooped posture with flexion of neck and trunk
• En bloc turning - turns without normal torso rotation

Non-Motor Symptoms (equally important!)

• Depression - most common psychiatric disturbance in PD; may predate motor symptoms
• Dementia (late feature; 15-40% of patients)
• Visual hallucinations (up to 40% of patients, often medication-induced)
• Autonomic dysfunction: constipation, orthostatic hypotension, bladder dysfunction
• Sleep disturbances: REM sleep behavior disorder (early marker)
• Anosmia (loss of smell - often a very early symptom)
• Dysphagia (swallowing difficulty, increases aspiration risk)

6. Basal Ganglia Pathways - Direct vs. Indirect

7. Diagnosis

• Cardinal features (TRAP)
• Asymmetrical onset (usually one side first)
• Response to levodopa

• No definitive blood test
• DaT SPECT scan (dopamine transporter imaging) - shows reduced dopamine uptake in the striatum
• MRI brain - usually normal in idiopathic PD (used to rule out other causes)

• Early postural instability
• Symmetrical onset
• Rapid progression
• No response to levodopa

8. Treatment - Pharmacology

A. Levodopa + Carbidopa (First-line, Gold Standard)

• Levodopa = metabolic precursor of dopamine; crosses the blood-brain barrier (dopamine itself cannot cross)
• Carbidopa = peripheral DOPA decarboxylase inhibitor; prevents conversion of levodopa to dopamine in the periphery
• Together: more levodopa reaches the brain, dose of levodopa is reduced 4-5 fold, peripheral side effects (nausea, vomiting, arrhythmias) are greatly reduced

• On-off phenomenon - unpredictable motor fluctuations
• Wearing off - effects diminish before next dose
• Dyskinesias (involuntary writhing movements)
• Nausea, vomiting, orthostatic hypotension
• Visual hallucinations, confusion (especially in elderly)

B. Dopamine Receptor Agonists

• Directly stimulate dopamine receptors in the striatum
• Longer acting than levodopa
• Used as monotherapy in early PD or adjunct to levodopa
• Useful when levodopa response fluctuates

C. MAO-B Inhibitors (Selegiline, Rasagiline)

• Inhibit monoamine oxidase type B - the enzyme that breaks down dopamine in the brain
• Reduce dopamine degradation → more dopamine available
• Selegiline may have mild neuroprotective effects

D. COMT Inhibitors (Entacapone, Tolcapone, Opicapone)

• Inhibit catechol-O-methyltransferase - enzyme that metabolizes levodopa in the periphery
• Used to address "wearing-off" phenomena with levodopa-carbidopa
• Tolcapone can cause hepatic necrosis (liver monitoring required); largely replaced by entacapone

E. Anticholinergics (Benztropine, Trihexyphenidyl)

• Block excess ACh activity in the striatum (restoring DA/ACh balance)
• Especially useful for tremor and rigidity
• Side effects: dry mouth, blurred vision, urinary retention, constipation, confusion (avoid in elderly)

F. Amantadine

• Antiviral drug found to have antiparkinsonian effects
• Increases dopamine release, blocks reuptake, and has NMDA receptor antagonism
• Reduces dyskinesias; useful in early mild PD

G. Surgical Treatment

• Deep Brain Stimulation (DBS) of the subthalamic nucleus or globus pallidus interna
• For patients with advanced PD who do not respond adequately to medications

9. Quick Comparison: PD vs. Drug-Induced Parkinsonism

10. Key Points to Remember for Exams

1. Site of lesion: Substantia nigra pars compacta
2. Neurotransmitter: Dopamine deficiency (relative acetylcholine excess)
3. Pathological hallmark: Lewy bodies (alpha-synuclein inclusions)
4. Classic triad (or tetrad - TRAP): Tremor, Rigidity, Akinesia, Postural instability
5. Tremor type: Resting, "pill-rolling", 4-6 Hz
6. Rigidity type: Cogwheel
7. Gait: Festinating (shuffling, short steps)
8. Facial appearance: Masked facies (hypomimia)
9. Writing: Micrographia
10. Drug of choice: Levodopa + Carbidopa
11. Why carbidopa? To prevent peripheral conversion of levodopa; reduces dose and side effects
12. Drug-induced parkinsonism: Antipsychotics (haloperidol, phenothiazines) - block D2 receptors
13. Surgical option: Deep Brain Stimulation (DBS)